Propylamine type antihistamines



Patented July 22, 1952 PROBYLAMIN E TYPE AN TIHISTAMINE S Nathan Sperber, Bloomfield, N. J., Domenick Papa, Brooklyn, N. Y., and Erwin Schwenk, Shrewsbury, Mass., assignors to Schering Corporation, Bloomfield, N

New Jersey J., a, corporation of No Drawing. Application July 17, 1950,

' Serial No. 174,358

11 Claims. 1

The invention relates to the manufacture of new substances which have been found to be highly effective against histamine-induced allergic reactions.

We have found that heterocyclic substituted aliphatic amines of the general formula wherein X represents a heterocyclic group which may be substituted by lower alkyl, lower alkoxy, chlorine or bromine, particularly pyridyl and substituted pyridyl groups, n is an integer not less than 2 and notmore than 4, R represents an alkyl, aryl, aralkyl, cycloalkyl or heterocyclic group or a chlorinated or brominated derivative of such groups, and R1 represents a dialkylamino, "'N-piperidino, N-morpholino or imidazolino group," and the salts thereof with inorganic and organic acids possess to an extremely high degree anti-histaminic and anti-anaphylactic activity. The aryl, aralkyl and heterocyclic groups may be substituted by lower alkyl, alkoxy and 'dialkylamino groups, and the heterocyclic groups may be attached to the tertiary carbon by a methylene group.

Compounds of the invention may be made for example by condensing a heterocyclic alkane compound, such as 2- or l-ibenzylpyridine, with the appropriate dialkylaminoalkyl halide, haloalkylimidazoline, haloalkylpiperidine or haloalkylmorpholine in the presence of an alkali metal amide, hydride or alkoxide, such as sodium or potassium amides, hydrides and alkoxides, or

organometallic compounds of alkali and alkaline earth metals such as alkali metal alkanes and Grignard reagents, for example, butyllithium, ethyl magnesium bromide, lithium diethylamide and triphenylmethyl sodium, as condensing catalyst.

The heterocyclic alkane compounds which may be utilized in making the compounds of the in-' vention may be represented by the general formula XR1R2 I wherein X represents aheterccyclic group which may be substituted by lower alkyl, lower alkoxy, chlorine or bromine, R1 is a saturated aliphatic group, and R2 is a member of the group consisting of alkyl, aryl, aralkyl, cycloalkyl and heterocyclic groups and lower alkyl, alkoxy, dialkylamino, chloro and rbromo substitution products thereof.

For example, 2- or 4-benzylpyridine maybe condensed with vfl-dimethylaminoethyl chloride: to give 3phenyl-3-(2pyridyl) N,N dimethylpropylamine and 3-pheny1-3-(4-pyridyl) -N,N- dimethylpropylamine, respectively.

The 2- and 4-benzylpyridines are readily obtained by the condensation of benzyl chloride with pyridine in the presence of a catalytic amount of copper powder. Separation of the isomers is effected by fractional distillation. In place of benzyl chloride substituted derivatives such as p-methoxy-, p-methyl, and p-isopropyl-benzyl chloride may be used.

Heterocyclic alkyl halides, such as Z-thienylmethyl chloride, may also be used in place of the benzyl chloride.

A useful method of obtaining intermediates for the compounds of the invention comprises the condensation of aldehydes,,such as 2-thiophenealdehyde with an organo-metallic compound 'of pyridine and reducing the resulting carbinolto the corresponding substituted methane;

A further method of obtaining the compounds of the invention is by the reduction of arylor heterocyclicpyridyl a,;3-ethylenes to the corresponding substituted ethanes and condensation of the ethanes with a dialkylaminoalkylhalide or a haloalkylimidazoline in the presence of butyl-j lithium, sodamide or potassium amide. r 1' Other methods for preparing the compounds, of the invention include the condensation of 2- thienylmethyl chloride with apicoline in the presence of potassium amide to, give 1-(2- pyridyl) 2 (2-thienyl),ethane which isthen brominated to the corresponding 5-bromothienyl' compound. a-Picoline may be similarly condensed with 2-chloromethyl 5 bromothiophene: to give the 1-(2-pyridyl) -2-(5-bromo-2-thienyl) ethane directly. The latter. compound may be then condensed, for example, Withfi-dimethylamino ethyl chloride in the presence of sodium or potassium amide to give 4- (5-bromo-2- thienyl) 31- (2 pyridyl)-N,N-dimethylbutylamine.

In place of 2-chloromethylthiophene and its bromo derivative, other heterocyclic and aryl alkyl halides may be used. For example, pbromoor p-chloro-benzyl chloride and B-(Z- pyridyl) -ethyl chloride can be suitably employed in this type of condensation reaction; With 2- (chloromethyl) imidazoline and the. 1'" '(2"- thienyl) -"2'- (Z-pyfidyDethane, 3-(2-thienyl) -12- (2-pyridyl) l (Z-imidazolinyl) -'propane' is'iob tained.

The compounds of the invention may alsofbe made by the hydrolysis and decarboxylation of the nitriles of the general formula R1 is a member of the group consisting of dialkylamino, piperidino, morpholino and imidazolinyl groups, R is a member of the group consisting of alkyl, aryl, aralkyl, cycloalkyl and heterocyclic groups and alkyl, alkoxy, dialkylamino, chloro and bromo substitution products thereof.

When the nitriles are treated with a strong 1 7 acid, an alkali metal amide, or an organometallic compound such as the alkali metal alkanes and alkyl magnesium halides, the nitriles are hydrolyzed and decarboxylated to the compounds of the invention as illustrated by the following Suitable nitriles for use in making the compounds of the invention may be made by:

(a) condensing a pyridyl, halide with an alkane, or substituted alkane, nitrile to form a pyridyl alkane nitrile and thereafter condensing the latter product with a dialkylaminoalkyl halide, a piperidinoalkyl halide, a morpholinoalkyl halide, or an imidazolinylalkyl halide;

(b) condensing an alkane, or substituted alkane, nitrile with a dialkylaminoalkyl halide, a piperidinoalkyl halide, a'morpholinalkyl halide, or an imidazolinylalkyl halide, and condensing the product with a pyridyl, or alkylpyridyl, halide; or

(9) condensing in one operation an alkane, or substituted'alkane, nitrile and a pyridyl, or alkylpyridyl, halide with a dialkylaminoalkyl halide, a piperidinoalkyl halide, a morpholinoalkyl halide, or an imidazolinylalkyl halide.

The condensations are advantageously effected by heating the reactants in an organic solvent, such as toluene or xylene or in liquid ammonia, in the presence of condensation catalysts, such as alkali metals, alkali metal amides, alkali metal alkoxides, or alkali metal organo compounds, for example, butyllithium or triphenylmethyl sodium.

The following specific examples are illustrative of the methods and products. of the invention:

EXAMPLE I 3-phenyZ-3- (Z-pyridyl) -N,N-dimethylpopylamine To 1.0 mole of potassium amide in 3 liters of liquid ammonia, is added 1.0 mole of Z-benzylpyridine. After minutes, 1.1 moles of fi-dimethylaminoethyl chloride are added. The ammonia is allowed to evaporate and the reaction product decomposed with water and ether extracted. sulfate and after evaporation the residue is disor alkylpyridyl,

. pound of this example is obtained as a viscous,

The ether layer is dried over sodium are made alkaline with gaseous ammonia. 'dimethoxyphenyl pyridyl carbinol is extracted 4 tilled, giving the 3-phenyl-3-(2-pyridyl)-N,N- dimethylpropylamine, B. P. 139-142" C./12 mm.

EXAMPLE II 3- (2,3-dimethoxyphenyl) -3- (Z-pyr'idgl) -N,N-

dimethylpropylamine 2,3 dimethoxyphenyl-(Z-pyridyl)carbinol is prepared by the reaction of 2,3-dimethoxybenzaldehyde and picolinic acid as follows:

A mixture of ten parts of 2,3-dimethoxybenzaldehyde, four parts of picolinic acid and twentyfive parts of cymene are'heated for approximately 4-6 hours at 170 C. Upon cooling,

the reaction product is extracted with aqueous hydrochloric acid and the resulting acid extracts The with ether, the ether Washed with water, dried, and, after removal of the ether, the residue is distilled.

To a solution of ten parts of the dimethoxyphenyl pyridyl carbinol in fill'parts of anhydrous benzene cooled to 0' 0., there is added dropwise 6.5 parts of thionyl chloride. After the addition is completed, the reaction is allowed to reach room temperature. After standing for several hours, the excess thionyl chloride is cautiously decomposed with 10% potassium carbonate solution so that the resulting mixture is strongly alkaline. The benzene layer is separated; dried over sodium sulfate, filtered and vacuum concentrated. The resulting deep red residue necked flask provided with a condenser and 50 parts of glacial acetic acid added. With stirring, 11 parts of zinc dust are added with external cooling, ifnecessaryu 'After stirringand heating for six hours, the reaction mixture is worked up in the known manner to yield the 2,3-dimethoxybenzylpyridine. Condensation of this benzylpyridine with ,5-dimethylaminoethyl chloride is carriedout as described for the corresponding unsubstituted compound. The comliquid boiling at approximately -200 C./12 mm.

7 EXAMPLE III I 3- (3,4 dimethomyphenyl) -3-(2 pyridyl) -.N,N- dimei'hylpropylamz'ne This compound is prepared as described for the 2,3-isomer using veratraldehyde in place ofthe 2,3-dimethoxybenzaldehyde.

EXAMIPLE IV 3-(2,4-dichlorophenyl)-3-(2-pyridyl) N,N dimethylpropylamine This compound is obtained in accordance with the instructions of Example II when 2,4-dichlorobenzaldehyde is substituted for the 2,3-di- 'methoxybenzaldehyde. The propylamine is obtained as a viscous yellow liquid.

EIIAMIPLE V methylpropylamine is transferred to a one-liter, threeamide .in liquid ammonia with p-N-piperidinoethyl chloride to yield the compound of this example. It is a viscous yellow 160-165 C./1-2 mm.

EXAMPLE VII 3-phenyZ-3- (Z-pyridyl) -N-morpholinopropane By substituting p-N-morpholinoethyl chloride for B-N-piperidinoethyl chloride in Example VI, the compound' of this example is obtained.

EXAMPLE VIII liquid boiling at dimethylamine By substituting p-dimethylaminobenzaldehyde for 2.3-dimethoxybenzaldehyde usedin Example-- II, the propylamine of this example is obtained as a yellow, somewhat viscous liquid b iling at 183-185 C./1.5 mm. 1

EXAMPLE IX 3- (s-ammophenyb -3-(2-pyridyl) -N,1vdimethyZpropg Zamine This substance is obtained from the compound of the preceding example by treatment with acetic anhydride according to the known methods.

EXAMPLEXI 4 -(5-B1'om0-2-thien11 Z)-3-(2 pyridyl) -N,N dzmethylbutylamine' 1-(2-pyridyD-2-(2 thienyl) ethane. To 1.0

mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of a-picoline, and after fifteen minutes, 1.1 moles of 2-thieny1methyl chloride. The ammonia is allowed to evaporate. The reaction product is decomposed with water, ether extracted and the ether layer extracted with dilute HCl. The acid layer is made alkaline with ammonia and. the oil which separates is ether extracted. The ether layer is dried over sodium sulfate, concentrated and the residue distilled at 106-110 C./0.5 mm.

i-(5-b1'omo-2-thz'enyl) -2- (2- pyridyl) ethane- To a cooled solution C.) of 1-(2-thienyZ)-2- (2-pyridyl)-ethane and 21 cc. of acetic acid is added-'3 cc. of bromine in 45 cc. of acetic acid with stirring. After one hour, the reaction product is made alkalinewith ammonia and the oil which separates is ether extracted, the ether layer is dried over sodiumsulfate, concentrated and the residue distilled at 0.5 mm., B. P.

4-(5 -bromo-2-thz'enful) -3-(2-pyridyl) -N,N dimethylbutyldmine.To' 1.0 mole of potassium amide in 3 liters of liquid ammonia is added 1.0 mole of 1-(5-bromo-2-thienyl) 2 (2 pyridyl) ethane. After minutes, 1.1 moles of B-dimethylaminoethyl chlorideis added. The ammonia is allowed to evaporate. The reaction mixture is worked up in the manner described in the previous examples and after, distillation alight yellow oil'is obtained, boiling at: 145,-148 C./0.5

The compound of this example may also be prepared by fcondensinga-picoline with 5-bromothienyl-Z-methyl. chloride and condensing. the. product with fi-dimethylaminoethyl ch1oride...;=.'=

EXAMPLE IHI 4-(5-chl0ro 2 tbienyl) -3- z py idyb-zviv-d a methylbutylamine This compound is made by the procedure used for the bromo compound. It is a pale yellow liquid, B. P. -144 C./0.5 mm.

EXAMPLE XIII 3-( Z-pyrzdyl) -N ,N -dimethyloctylamine In an atmosphere of nitrogen 1- mole of'2-(n hexyl) -pyridine in ether is addedtol mole of butyllithium in anhydrous ether. After refluxing the reaction for several hours, 1.1 molesof.

5-dimethylaminoethyl chloride in ether is added and the reaction mixture refluxed for six hours. Thereactionproduct is decomposed with Water and the etherlayer separated, dried over sodium sulfate andthe ether distilled off. The residue is distilled at 1.5 mm.,,B. P. 104105 C.

' EXAMPLE XIV 3.-cycl o hemgjl-3-(2 pyridyl) -N,N 9 dimethylpropylamine To 1.0 mole-of 2-pyridyl-N,N-dimethylpropylamine in ether is added 1.0 mole of butyllithium in anhydrous ether in an atmosphere of nitrogen. "After several hours of refluxing, 1.1 moles of' cy'clohexyl bromide in ether is added andthe resulting mixture refluxed for six hours. The reaction product is decomposed'with water, the

etherlayer separated and extracted with dilute- HCl; The acid layer is made alkaline with'a'm monia and theresulting oil is ether extracted. The ether'layer is dried over sodium sulfate, concentrated and the residue distilled, B. P. C./2 mm.

EXAMPLE XV The compoundof this example is made by condensing 2-benzylpyridine with 2 (chloro methyDimidazoline. I 1

The intermediate, 2-(chloromethyl)imidazoline, may be made by the reaction of ethyl'chloroacetimidate hydrochloride (McElvain 8: Nelson,

J. Am. Chem. Soc. 64, 1825 (1942)) and ethylene EXAMPLE XVI z-(z-pyridyz) 1 -bhenyZ-3-(Z-imidaeolinyl)propane To 1.1 moles of potassium amide in 3 liters of liquid ammonia is added 1 mole of adihydTOSti1-' 7v bazole. After fifteen minutes, lrmole of 2-(chloromethyl)imidazoline is added. The ammonia is allowed to evaporate and the reaction mixture is decomposed with Water. Thereaction mixture is ether extracted, the ether layer washed with.

EXAMPLE XVII 3-(2-thienyl) 3 (Z-pyrz'dyD -N,N -d2methylpropi/Zamine The requisite intermediates, (2-thienyl) -(2- pyridyl) -carbinol and 2-(2.-thienyl) pyridine are made as follows: Y

In an atmosphere of nitrogen, 39.5 g. of n-butyl chloride is added to a stirred mixture'of 6 g. of lithium and 250 cc. of anhydrous ether. When the lithiumis completely reacted, the mixture is cooled to 40 C. and a solution of 39.5 g. of 2-bromopyridine in 50 cc. of ether is added. Throughout the addition, the. temperature is maintained at -40 C. The reaction mixture is stirred for minutes and 33 g. of Z-thiophenealdehyde is added without allowing the temperature to arise above -30 C. The reaction temperature is then allowed to rise to 15 C. and the mixture is stirred an additional 45 minutes. The reaction mixture is poured into dilute hydrochloric acid and ice, the acid layer separated andafter basifying-with gaseousammonia, the

oily layer is extracted with ether. The ether extracts are dried and after removingthe solvent,

the; residue is distilled. The (Z-thienyD-(Z- pyridyl) -carbinol boils at 138-140" C./1 mm. The carbinol may also be made from Z-pyridyl magnesium bromide and Z-thiophene-aldehyde by the conventional Grignard synthesis.

The 2-(2-thenyl) pyridine is made as follows: To a stirred, cooled solution of 49.5 g. of (2-thienyl) -(2-pyridyl) -carbinol in 300 cc. of benzene, there is added slowly 34 g. of thionyl chloride keeping the temperaturebelow C. The reaction mixture is stirred-forone hour at room temperature, then cooled, and made alkaline with dilute sodium hydroxidesolution, keeping the temperature below C. The benzene layer is separated, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is dissolved in 300 cc. of glacial acetic acid and the solution added to a one liter, three necked flask equipped with a stirrer'and condenser. To the acetic acid solution, there is added in portions 40 g. of zinc dustand the reaction mixture is stirred and heated at -95 C. for six hours. The zinc salts are filtered off, the filtrate cooled and then made slightly alkaline with dilute sodium hydroxide solution. The alkaline mixture is extracted with ether, the ether extracts dried and then concentrated. The residue is distilled, B. P. 103-106 C./l mm. H

To potassium amide (from 3: 9 -g. of potassium) in 500 cc. liquid ammonia, there is added 17.5 g. of 2-(2-thie'n'yl) pyridine; The red solution is stirred for 10 minutes, and 15 g. of ,B-N,N-dimethylaminoethyl chloride added. The reaction mixture is stirred until the ammonia has evaporated and then decomposed with 200 cc. of water. The oily layer is extracted with ether, the ether extracts dried and then evaporated. The residue, 3-(2-thienyl)-3-(2-pyridyl)-N,N-

' liquid, B. P. 149-152? c./1 mm.

dimethylpropylamine, distills as a pale yellow Oil, B. P. -128 C./1 mm.

EXAMPLE XVIII 3 3 thienyl) s 2 pyridyl) N,N-dimethylpropylamin By the same sequence of reactions as described for the 2-isomer of Example XVII, this propylamine is obtained as a yellowish clear liquid, B. P. 134-137 C. at 2-3 mm. The intermediates, (3-thieny1) (2-pyridyDcarbinol and 2-(3- thienyhpyridine, boil at 141-14? C./1 mm. and 105-107 C./0.5 mm. respectively.

EXAMPLE XIX N,N-dim ethylp1"opylamine Condensation of 5-methyl-2-thiophenealdehyde and 2-bromopyridine as-described in Example XVII yields the (5-:methyl-2-thieny1) (2- pyridyDcarbinol boiling at 146-150 C./1 mm. Treatment of this carbinol' with thionyl chloride and subsequent reduction of the chloride with zinc dust gives the 2-(5-methyl-2 -thienyl)pyridine boiling at 108-111 C ./0.5 mm. Alkylation with dimethylaminoethyl chloride in accordance with the instructions of Example ,XVII yields the propylamine boiling at134-13'7" C./1 mm.

EXAMPLE Xx 3 2 thienyl) 3 2 pyridyl) N,N dzethylpropylamine By the procedure of Example XVII using B-diethylaminoethyl chloride in place of the corresponding dimethyl compound, the propylaminechloride as described in the proceeding examples, B. P. 138-142" C./2-3 mm.

EXAMPLE XXII. v

3 5 chloro -'2 thienyl) 3 2 pyridyD- N,N-dz'methylpropylamine This chloro compound; "is prepared-from 5-- chloro-2-thiophenealdehyde as described in Example'XVII, B. 1?. vizc./1-2 mm.

EXAMPLE XXIII 3 -'(3 methyl 5 chloro 2 meal) 3 2- pyridyl) N,N dimethylpropylamine By a similar sequence. of reactions as in Example XVII, this propylamine is obtained from 3- methyl-B-chloro 2 thiophenealdehyde. The substance is asomewhat viscous,

EXAMPLE XXIV 3 (2 thienyZ 3 (6' methyl -2 pyridg D- N,N-dimethylp r1opylamine By using 6-methyl-2- -bromopyridine in place of bromopyridine as in Example XVII, this propylamine is obtained asa yellow-orange liquid, B;P. 133-137 C./ 1-2 mm.

pale yellow 3 phenyl 3 v 7' 7 EXAMPLE XXV s methyl 2 thienyl) 3 2 pyridyl) N-piperz'dinopropane The 2-(5-methyl-2-thienyl)pyridine of Example XIX is condensed with p-N-piperidinoethyl chloride in accordance with the instructions of Example XVII. This tricyclic base is a yellow liquid boiling at 140-144 C./ 0.5-1 mm.

EXAMPLE XXVI 3- (5 -hromo-2-thienyl) -3- (Z-pyridyl) -N,N-

dimethyZprom Zamine The reaction of 5-bromo-2-thiophenealdehyde and bromopyridine as described in Example XVII gives the (5-bromo-2-thienyl) (2-pyridyl) carbinol, B. P. 152-155 C./1 mm. Replacement of -the hydroxyl by hydrogen and the subsequent condensation of this compound with B-dimethyl aminoethyl chloridegives the compound of this example, BJP. 150-155 C./1-2 mm.

EXAMPLE XXVII (2 pyridyl) N,N-dimethylpropylcmine To 400 g. of a-phenyl-a-(,B-dimethylaminoethyl).-2-pyridylacetonitrile there is added 2,000 g; of 80% sulfuric acid. The mixture is heated with stirring at 140150 C. for 24 hours. decomposing with ice and water, the aqueous sulfuric acid solution is made alkaline with ammonia gas. The oil which separates out is extracted with ether, the extract is dried, and, after removing the ether, the residue is distilled giving the 3-phenyl-3-(2-pyridyl)-N,N-dimethylpropylamine, B. P. 139-142 C./1-2 mm.

In addition to the hydrolysis and decarboxyla- ,tion of the nitriles and 80% sulfuric acid, the conversion maybe efiected in other ways. For example:

(a) One part of the nitrile and ten parts of 48% hydrobromic acid are refluxed for a period of 50-60 hours. The aqueous hydrobromic acid is removed in vacuo. The residue is made alkaline with gaseous ammonia and the oil which separates is extracted with ether. The ether residue is treated with a saturated alcoholic solution of picric acid heated to boiling and filtered. The insoluble picrate is washed with boiling alcohol. This purification process removes any starting material which, unlike the tertiary amine, forms an alcohol soluble picrate. The insoluble picrate is then decomposed with dilute sodium hydroxide, the amine is isolated by ext traction with ether and purified by distillation.

(b) To one part of the nitrile there is added five parts of 80% sulfuric acid and one part of 48% hydrobromic acid. The mixture is heated at a temperature of 130140 C. for about 30-40 hours and the reaction mixture Worked up as in method (a).

(0) One part of the nitrile is refluxed with concentrated hydrochloric acid for about 60 hours. The amine thus formed is isolated and purified as described under method (a) (d) In a 500 cc. 3-necked flask is suspended 0.2 mole of sodamide in 150 cc. of xylene. To the suspension is added 0.1 mole of the nitrile and the reaction mixture is refluxed with stirring for approximately -20 hours. The excess sodamide is decomposed with water, the xylene layer separated and concentrated in vacuo. The residue is fractionated to yield the substituted propylamine.

After is stirred for several hours.

(e) To cc. of dryether, there is added 0.6 mole of lithium cut in small pieces. To the stirred mixture is added 0.28 mole of ethyl bromide, allowing the ether to reflux gently. The reaction mixture is refluxed for one hour, cooled to -25 C. in an acetone-Dry Ice bath and 0.1 mole of the nitrile is added dropwise. The deep red mixture is allowed to warm up to room temperature and The complex is decomposed with ice and hydrochloric acid, the acid layer" separated and made alkaline with ammonia. The resulting oil is ether extracted, dried and concentrated. The residue is fractionated to yield the compound of this example.

(f) To a 500 cc., 3-necked flask containing '100 ce. of anisole and 0.25 mole of magnesium turnings, there is added 0.285 mole of ethyl bro- After the formation of the Grignard reagent is complete, 0.20 mole of the nitrile in 100 cc. of anisole is added, keeping the temperature between 50-60 C. The temperature is kept at about 60 C.,for an additionaltwo hours. The reaction mixture is decomposed with 2N hydrochloric acid, the acid layer separated, and then made alkaline with ammonia. The resulting oil is extracted with ether, the ether extracts dried and concentrated. The residue is fractionated to yield the propylamine.

The following compounds having substantial anti-histaminic activity may be made from the corresponding nitriles by the methods of Example XXVII:

3 -phenyl-3-(2 pyridyl) N,N diethylpropy1- amine, a yellow oil boiling at 156 C./1 mm., from e-phenyl-a (,6 diethylaminoethyl) 2 pyridylacetonitrile.

4-phenyl 3 (2 pyridyl) N,N dimethylbutylamine, boiling at about 135 (L/0.5 mm., from a-benzyla 8 dimethylaminoethyl)-2-pyridylacetonitrilelpropylamine, a pale yellow oil boiling at 1 25-128 C./1 mm., from a- (2-thienyl) a- (fl-dimethylami- ,noethyl) -2-pyridylacetonitrile.

4-(2 thienyl) 3 (2-pyridyl) N,N-dimethylfbutylamine, boiling at -133 C./0.1 mm., from a.(2 -thiny1methyl) a (p-dimethylaminoethyl) .Z-Dyridy-lacetonitrile.

{3-(p methylphenyl) 3 ,(2-pyridyl) N,N-dimethylaminoethyl) -2-pyridylacetonitrile.

3-(p methoxyphenyl) 3 (2-pyridyl) N,N- dimethylpropylamine, boiling at about 1 37-142 C./0.5 mm., from a-(p-methoxyphenyl) -a( 3-di methylaminoethyl) -2-pyridylacetonitrile.

BI- (p isopropylphenyl) 3 (2 pyridyl) N,N-dimethylpropylamine, boiling at 144-14'7 C./-1 mm., from a-(p-isopropylphenyl)-a-(p-dimethylaminoethyl) -2-pyridylacetonitrile.

3 phenyl 3 (6 methyl 2 pyridyl). N,N-dimethylpropylamine, boiling at 171-175 C./1 mm., from a-(B-dimethylaminoethyl)ea- (6-methyl-2-pyridyl) -phenylacetonitrile.

3 (p-bromophenyl) 3 (2 pyridyl) N,N- dimethylpropylamine, boiling at about 147-152 C./0.5 mm., from a-(p-bromophenyl)-a-(/3-dimethylaminoethyl) -2-pyridylacetonitrile.

4 phenyl 4 (2 pyridyl) 2 (dimethylamino) -'butane,' from a-phenyl-a-(2-pyridyl) -a- (dimethylamino) -valeronitrile.

4 phenyl 4 (2 pyridyl) N,N dimethylbutylamine, i from 'a-phenyl-ir (Z-DYlidYDf-u- (dimethylaminoethyl) -valeronitrile.

11 o 3 cyclohexyl 3 (2 pyridyl); --N;N dimethylpropylamine, from a-CYCIOhBXYl-a-(fi-dimethylaminoethyl) -2-pyridylacetonitrile.

J- dimethylbutylamine, from a-(p-bromobenzyl) -u.-

( s-dimet-hylam-inoethyl) -2-pyridylacetonitrile.

3 (p-chlorophenyl) -3 (2 pyridyl) N,N dimethylpropylamine from a- (p-chlorophenyl) (18- dimethylaminoethyl) 2 pyridylacetonitrile. v I 3 -(o chlorophenyl) 3'- (2 pyridyl) N,N dimethylpropylamine from a-(o-chlorophenyl)- a 5 (B ;dimethylaminoethyl) 2'- pyridylace- .tonitrilea EXAMPLE .XXVIII 3,3-bis-l2-Pyridyl) N ,N-dimethylpropylamine o-orhommorm, H

' 7 j Preparation of a,a-bis-(2-pyridyl)acetonitrile. the ammonia is replaced by 800 cc. of toluene. In a one-liter, 3-necked flask equipped with stirrer and condenser, 51 g. of sodium is converted to sodamide in the usual manner and In a five-liter, B-necked flask equipped with a stirrer, condenser and dropping funnel, are 'placed 227 g. of 2-chloropyridine, 41g. of acetoni trile and one liter of toluene. The solution "is warmed to 100 C. and a stirred sodamide suspension from 51 g. of sodium is refluxed for an additional 4 hours. The reaction mixture is decomposed with Water and the organic layer is separated and extracted with dilute hydrochloric acid; The acid layer is made alkaline with ammonia and the resulting oil is taken up in benzene. The benzene layer is dried over "sodium sulfate, filtered and concentrated. The residue distills at 182-192" C./1 mm. Yield: 94 g. The solid material is recrystallized from benzenepetroleum ether, M. P.,137-139 C.

composed with water and the organic layer is vacuum-concentrated. The residue is fractionated .as'a deep red, viscous oil, B. P. 165l72 C./0.5 mm.

Preparation of 3,3-bvls-(2-pyridyl) -N,N-dimethgllpropylamine-In a 500 cc., 3-necked flask equipped with a stirrer, condenser and thermom- V eter are placed 25 g. of a,a-biS-(2-IJYIldY1)-a (N,N-dimethylaminoethyl) acetonitrile and 135 g. of 70% sulfuric acid. The stirred solution, is heated at 130 C. for 5 hours until the evolu- .tionof carbon dioxide has'ceased. The solution ,is poured on ice, made alkaline with ammonia and the resulting oil is ether extracted. The

12 ether layer is dried over' sodium sulfate, filtered and evaporated. The residue is fractionated. B. P. 129-132 0.70.5 mm;

EXAMPLE xxIx 3-(2-furyl) -3-(2-pyridyl) -N,N-dimethylpropylamine The intermediate, Z-furylacetonitrile, is obtained from furfura l by the Well-known reaction with rhodanine (J. A. C. S. 5'7, 1126, (1935)). To a mixture of 0.5 mole of.2fur.ylacetonitri1e, 0.5 moleof 2-chloropyridine and 0.5'moleof .;3-N,N- dimethylaminoethyl chloride in 500 cc. of toluene there is added one mole of sodamide suspended in 350 cc. of toluene. The reaction mixture is heated at about 100 C. for several hours and then cautiously decomposed with water. The toluene layer is extracted with dilute hydrochloric acid and the acid extracts then made alkaline with gaseous ammonia. The resulting oil is extracted with ether. The ether extracts are washed and after removing the ether, the crude trisubstituted acetonitrile is treated either with 80% sulfuric acid or with sodamide in xylene solution to yield the propylamine of this example.

EXAMPLE I 3- (Z-pyridyi) -3- (Z-thiazyl) -N,N-dimethylpropylamine Equations for the preparation of this compound are given as equations v1, 2; and 3:

(III) Equation 1 illustrates the simultaneous conchloric acid.

one for the condensation reaction and one to liberate the free amine and neutralize the hydro- The tri-substituted acetonitrile (IV) on treatment with a strong mineral acid .such as 80% sulfuric acid readily loses the CN group; to yield the desired substituted proplyamine (V). Removal of the CN group is also effected by treatment of the nitrile (IV) with one equivalent of sodamide in either boiling toluene or xylene solution.

Equation 2 illustrates an alternate method for securing the disubstituted nitrile (III). Acetonitrile is condensed with one equivalent of sodamide in toluene solution with 2-chloroor 2-bromopyridine to yield the substituted acetonitrile (VI), which on further treatment with one mole of sodamide and one mole of 2-bromothiazole yields the nitrile (III).

Equation 3 illustrates an alternate method for obtaining the trisubstituted nitrile (IV) In most cases, this method is to be preferred; since, by one step, the intermediate (IV) is obtained in contrast with the other methods which require two steps. The requisite a-N,N-dimethylaminobutyronitrile is readily made by the reaction of a-ChIOl'O- or .a-bromobutyronitrile with dimethylamine. In place of dimethylamine, other dialkyl amines may be used, such as diethyl, dipropyl, and dibutylamine.

The method illustrated in Equation 1 is carried out as follows: To one mole of acetonitrile "in 500 cc. of toluene, there is added 0.5 mole of 2-chloropyridine and 0.5 mole of 2-bromothiazole. The resulting mixture is then'heated to approximately 40-60" C. and a suspension of 'one mole, .of sodamide in 300 cc.- of toluene is cautiously added. Upon completion, the reaction mixture is heated for approximately three :hours at 100 C. and then cautiously decomposed with water. The toluene layer is processed for the nitrile-(III) as described in Example XXIX. Condensation with fi-N,N.-dimethylaminoethyl chloride to the nitrile (IV) iseffected using sodamide as condensing agent. The tri-substituted nitrile (IV) is used without further purification for the preparation of the propylamine (V). The latter reaction is carried out as follows: A mixture of 0.5 mole of the nitrile (IV), 0.5 mole of sodamide and 350 cc. of xylene is heated with stirring for about 8-l2 hours at 120- 140 C. After cooling the reaction mixture to 60 C., it is cautiously decomposed'with water and the xylene layer isolated. After washing and drying and removing the xylene, the propylamine (V) is purified by fractional distillation. There is obtained, as a very pale yellow, freeflowing liquid, the compound of this example boiling at 138-140 (IL/2mm.

The method illustrated by Equation 2 is carried out as follows: To one mole of acetonitrile in 500 cc. of toluene, there is added 0.7 mole of '2-chloropyridine. To this mixture 0.7 mole of sodamide is added at about 60 C. and the condensation completed as described above. The

crude 2-pyridylacetonitrile is used without distillation in the subsequent condensation with z-bromothiazole.

amine of this example.

, 1 The thus obtained disubstituted nitrile (III) is converted into the .propylamine (V) as described above.

.The method illustrated by Equation 3 is, carried out in essentially the same manner as the condensations described above. The simultaneous condensations may be made withv both' halides or a condensation with 2-chloropyridine may be the primary step, followed by condensation with 2-bromothiazole. It has been. found advantageous to isolate the product of the first condensation prior. to condensation with the second halide, The thus obtained tri-substituted;nitrile (IV) is then treated by the described methods to yieldthe propylamine'W). r r

3-(2-Pg/1id1/Z) -3- (Z-thiaeyl) -N,N-diethylpropylamin e This compound is prepared in exactly the same manner as described for the homologous dimethyl compound by substituting B-NN-diethylaminoethyl chloride in Example XXX.

EXAMPLE XXXIII 3,3-bz's- Z-Thz'azyl) N,N- dimethylpropylamine This compound is made by the condensation of acetonitrile with 2 moles of 2-bromothiazole in accordance with the method described for the corresponding bis-(Z-pyridyl) compound of Example XXVIII. The reaction may be illustrated by the following equation: v, v

H CHaCN J Condensation of the bis-(Z-th'ia'ZyDacetOnitrile With p-N,Ndimethylaminoethyl chloride as described in Example XXVIII yields the trisubstituted nitrile a,a.blS (Z-thiazyl) -;a.- (N,N- dimethylaminoethyl) acetonitrile, which without purification is treated with sulfuric acid. The resulting reaction mixture is worked up as described in Example XXVIII to yield the propyl- NaNH;

EXAMPLE xxxiv 4,4-bis- (2- Tliiazyl) -N,N-dimethylbutylamine This compound is made from a -bis- (2- thiazyl) acetonitrile and 'y dimethylamino- EXAMPLE zocxv 3 (2,-Pyrimidyl) -3- (Z-thiazyl) NJV dimeth /Z- pro pylamine The preparation of this compoundiscarrie d out essentially asdescribe'd in EquatiGns Qand-B that a ratio of one part of the 'trisubstituted ni-.

trile and three parts of 80% sulfuric acidat the given temperature gives yields of the final product exceeding 90%.

EXAlVLPLE XXXVI 2-dimethyZamino-4-(Z-pyrimidyl) -4- z -thiazyl) butane This compound is'made in the manner described in Example XXXV by substituting fl-N,N dimethylaminopropyl chloride for the B-N,N-dimethylaminoethyl chloride of the preceding example.

EXAMPLE XXX II I .3-(2-thiazyl) -s- (Z-thienyl) -N,N-dimethylpropylamine hours. The acid reaction mixture is worked up in accordance with the instructions of the previous example and the propylamine purified by fractional distillation.

EXAMPLE XXXVIII a-rz-thmzyz) -3- (Z-thienyl) -N-piperidinopropane f 1135; [substituting 8-N-piperidinoethyl chloride for the l3-N,N-dimethylaminoethyl' chloride in the preceding example, there is obtained the N- piperidino-substituted propane.

7 EXAMPLE XXXIX 3- (Z-pyrazyl) -3-(2-thiazyl) -N,N-dimethylaminopropwne Y 1 This compound is obtained bythe condensation of acetonitrile with 2-chloropyrazine followed by condensation with 2-bromothiazole. The intermediate disubstituted acetonitrile is then condensed with f1-N,N-dimethylaminoethyl chloride and the resulting nitrile treated with 80% sulfuric acid. .The Various reactions are carried out essentially as described in the previous examples.

7 EXAMPLEXL s- 2-mmzyz -3-(2-,furyl) -N,N-dimethylpropylamine By substituting 2-bromothiazole for the 2- chloropyridine of .Example XXIX, there is obtained the propylamine of this example.

EXAMPLE XLI H propylamine V a V This compound can be obtained as a pale yellow oil boiling at 154 C./2 mm. from 11-(2- thienyl) -a-(e-dimethylaminoethyl) -2 pyridylacetom'trile, which maybe made by substituting 2-chloropyridine for the 2-bromothiazole in the procedure of Example XXXVII.

EXAMPLE XLII 4- (5-bromo-2-thienyl) -3-(2pyridyl) -N,N- dimethylbutylamine fiJCHB CH3 (XIII) Compound (XI) .To 1.0 mole of'potassium amide in 3 liters of liquid ammonia is added 1.0 mole of api'coline, and after fifteen minutes, 1.1 moles of 2-thienylmethyl chloride. The ammonia is allowed to evaporate. The reaction product is decomposed with water, ether extracted and the ether layer extracted wih dilute HCl. The acid layer is made alkaline with ammonia.' and the oil which separates is ether extracted. The ether layer is dried over sodium sulfate, concentrated and the residue distilled, B. P. 106-110 C./0.5

Compound (XII) .1-(5-bromo-2-thieny1l)-2- (2-pyridyl) -ethane: To a cooled solution (10C.) of l-(2-thienyl) -2-(2-pyridyl) -ethane and 21 cc. of acetic acid is added 3 cc. of bromine in 45 cc. of acetic acid with stirring. After one hour, the reaction product is made alkaline. with ammonia and the oil which separates is ether extracted, the ether layer is dried over sodium. sulfate, concentrated and the residue distilled at 0.5 mm., B. P. 129-l33 C.

Compound (XIII) .-4-(5-bromo-2-thienyl) -3 (2-pyridyl) N,N-dimethylbutylamine: To 1.0 mole of potassium amide in 3-liters of liquid ammonia is added 1.0 mole of l-(5-bromo-2- thienyl)-2-(2pyridyl)-ethane. After 15minutes, 1.1 moles of p-dimethylaminoethylchloride is added. The ammonia is allowed to evaporate. The reaction mixture is worked up in the manner described in the previous examples and after distillation a light yellow oil is obtained, boiling at 145-148 C./0.5 mm. 1 p

XIV) wherein the bromo compound (XIV) is then alkylated as described.

EXAMPLE XLIII 4-( -chZoro-2-thienyl) -3-(2-pyr2'dyl) -N,N- dimethylbutylamine This compound is made by the procedure used for the bromo compound. It is a pale yellow liquid, B. P. 140-144 C./0.5 mm.

EXAMPLE XLIV 4-(2-thienyl) -.3- (Z-Mridyl) -N,N- dimethylbutylamine This compound, boiling at 130-133 C./0.1 mm., is obtained if the bromination step is omitted from the procedure of Example XLII. It may also be obtained from a-(2-thienylmethyl) -a.- (p-dimethylaminoethyl) 2 pyridylacetonitrile by treatment with strong acids.

The compounds of the invention may be used in the form of the free bases or in the form of the salts thereof with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids and organic acids,.such as salicylic, tartaric, maleic, succinic, citric, lactic and other aids.

The compounds may be used in a variety of forms, such as tablets for oral administration, creams for topical application, and injectible solutions. Preferably the salts of the compounds are used in the creams which may be of the usual formulations. The injectible solutions comprise non-toxic salts.

This application is a continuation-in-part of our application Serial No. 782,688 filed October 28, 1947, now abandoned, and contains subject matter in common with our applications Serial No. 20,108 filed April 9, 1948, now abandoned, and Serial No. 26,246 filed May 10, 1948, now Patent No. 2,567,245.

We claim:

1. Compounds of the general formula wherein X and R are each members of the group consisting of furyl, thiazyl, pyrimidyl, thienyl. pyrazyl and their lower alkyl, chlorine and bromine substitution products. R1 is a member of the group consisting of dialkylamino, N-morpholino, N -piperidino and imidazolino groups, m is selected from 1 and 0, and n is not less than 2 and not more than 4 and the acid addition salts thereof. f

2. Compounds as defined in at least one of X and R is thiazyl.

3. Compounds as defined in claim 1 wherein at least one of X and R is furyl.

4. Compounds as defined in claim 1 least one of X and R is thienyl.

5. Compounds as defined in claim 1 least one of X and R is pyrimidyl.

6. Compounds as defined in claim 1 and R are the same.

7. 3,3 bis (2 thiazyl) -N,N-dimethylpropyl amine.

8. 3 (2 pyrimidyl) 3 (2 thiazyl)-N,N- dimethylpropylamine.

9. 3 (2 thiazyl) 3 (2 thienyl) -N,N dimethylpropylamine.

10. 3 (2 thiazyl) 3 (2 thienyl) -N piperidinopropane.

11. 3 (2 thiazyl) 3 (2 dimethylpropylamine.

wherein at wherein at wherein X furyl) N,N-

NATHAN SPERBER. DOMENICK PAPA. ERWIN SCHWENK.

No references cited.

claim 1 wherein 

1. COMPOUNDS OF THE GENERAL 